3-halo-16beta-carbamyl-delta5-pregnen-20-ones



United States Patent 3-HAL0-165-CARBAMYL-A -PREGNEN--0NES Pierre Crabb, Mexico City, Mexico, assignor to Syntex S.A., Mexico City, Mexico, a corporation of Mexico No Drawing. Filed Apr. 13, 1962, Ser. No. 187,202

20 Claims. (Cl. 260-2395) 5 activity and which are also anti-estrogenic and anti- 15 androgenic agents, are represented by the following formulas:

In the above formulas X represents fluorine, chlorine or bromine; R and R each represent hydrogen, a lower alkyl, amino lower alkyl, lower alkyl amino lower alkyl, di-(lower alkyl)amino lower alkyl, aryl or aralkyl groups containing up to 8 carbon atoms; R and R together with the nitrogen represents a heterocycle such as pyrrolidine,

piperidine, morpholine or piperazine, which may or may not contain alkyl substituents.

The novel compounds of the present invention are prepared by the process illustrated by the following equations:

gfi i 25 In the foregoing formulas X, R and R have the same meaning as set forth hereinbefore.

In practicing the process outlined above, the starting 16fl-carbomethoxy-A -17a-pregnen-3p-ol-20-one (I) [prepared in accordance with Romo, Tetrahedron, 3, 37 (1958); the correct configuration was assigned by Mazur et al. Tetrahedron 7, 130 (1959)] is treated with tosyl chloride in pyridine, to produce the corresponding 3-t0sylate, which upon treatment with a mild base, such as potas sium acetate in a suitable polar solvent, such as acetonewater, yields 16/3 carbomethoxy 3,5-cyclo-17a-pregnen- 6/3-0l-20-one. The latter compound, upon treatment with hydrogen fluoride in a suitable solvent such as methylene chloride, furnishes .3fl-fiuoro- 16fi-carbomethoXy-A -17mpregnen-ZO-one (II: X=F).

Upon reaction of the starting compound (I) with a suitable chlorinating agent, such as phosphorus pentachloride, or a suitable brominating agent such as phosphorus pentabromide, there is obtained 3B-chloro-16/3-carbomethoxy-A -l7oz-pregnen-20-one (II: X=Cl) or 3/8- bromo 16,8-carbomethoxy A -17a-pregnen-20-one (II: X=Br).

The treatment of the 35-halo-16B-carbomethoxy-A 17a-pregnen-20-one derivatives (II) with ammonia or a primary or secondary amine, such as a lower alkyl amine, di-(lower alkyl)amin'e, amino lower alkyl amine, aryl amine, aralkyl amine or a cyclic amine such as piperidine or pyrrolidine, in a suitable solvent such as ethanol, for a period of time of the order of 6 to 12 hours, at a temperature at about C. to (3., furnishes the corresponding 35 halo 16p (amino) carbonyl-A 470:-

pregnen-ZO-One derivatives (III), which upon reaction in an alkaline medium, such as a solution of an alkali metal hydroxide in methanol, produce the corresponding A 475- pregnene derivatives (IV). V

The following specific examples serve to illustrate but are not intended to limit the scope of the present invention:

Example I A solution of 5 g. of 16fi-carbomethoxy-A -l7a-pregnen- 3,6-ol-20-0ne in 25 cc. of pyridine was treated with 2.5 g.

- of tosyl chloride and kept at room temperature for 24 hours, it was then diluted with waterand the precipitate separated by filtration, thus giving the 3-tosylate of 16ocarbomethoXy-A -17a-pregnen-3fl-ol-20-one.

A mixture of 4 g. of the latter product, 6, g. of potassium acetate, cc. of acetoneand 100 cc. of Water was refluxed for 6 hours. Then it was diluted with water and CH CH3 /E LQ 1 XQI i extracted with ethyl acetate. The organic extract was washed with water, dried over anhydrous sodium sulfate and evaporated to dryness. The residue was recrystallized from methylene chloride-methanol, to give 16,8-carbomethoxy-3 ,5 -cyclo- 1 7a-pregnen-6B-ol-20-0ne.

In a polyethylene flask, adapted with magnetic stirrer, there was dissolved 2.8 g. of 16fl-carbomethoxy-3,S-cyclol7oc-Pl6g1'l6Il-6fi-Ol-20-OI1C in 30 cc. of methylene chloride, the solution was cooled to C. and a solution of 12 g. of anhydrous hydrogen fluoride in 20 cc. of tetrahydrofurane cooled in a Dry-Ice acetone bath (70 C.) was added over a period of 20 minutes with constant stirring. The mixture was stirred at a temperature lower than 10 C. for 6 additional hours, then neutralized by cautiously adding a aqueous sodium bicarbonate solution and transferred to a separatory funnel. The organic layer was washed with water, dried over anhydrous sodium sulfate and concentrated until formation of an abundant precipitate. The mixture was cooled, the precipitate filtered and redissolved in hot ethyl acetate, the insoluble material was filtered ofl? and the filtrate cooled whereby there crystallized SB-fiuoro-16 3-carbomethoxy-A -17apregnen-ZO-one.

Example II To a solution of 5 g. of 16fl-carbomethoxy-A -17apregnen-3B-ol-20-one in 100 cc. of benzene, were added 5 g. of phosphorus pent-achloride and the resulting mixture was refluxed for 1 hour in the absence of moisture. It was then cooled, poured into water; the benzene layer was Washed with water several times, dried over anhydrous sodium sulfate and evaporated to dryness. Crystallization of the residue from acetone-hexane yielded; 35- chloro-16 8-carbometl1oxy-A -l7a-pregnen-20-one.

Example III 165 carbomethoxy A -17a-pregnen-3 B-ol-20-one was treated in accordance with Example II, except that phosphorus pentachloride was substituted by phosphorus pentabromide thus affording 3,8-brorno-l6 8-carbomethoxy-A -l7a-pregnen-20-one.

Example IV a 2 g. of 3fi-fiuoro-l6fi-carbomethoxy-A -l7u-pregnen-20- one, and a solution of 4 g. of dimethylamine in 100 cc. of ethanol were introduced into a tube, which was thereafter sealed and heated to 100 C. This temperature was maintained for 12 hours. The tube was then opened, and the resulting mixture was evaporated to dryness, under reduced pressure. The residue was recrystallized from acetone-hexane, thus yielding 3fi-fluoro-l6fi-(dimethyl carbamyl) -A 1 7oz-pregnen-20-one.

Example VI 36 fluoro l6,8-carbomethoxy-A -17a-pregnen-20-one was treated in accordance with Example V, except that dimethyl amine was substituted by piperidine, thus atfording 3,8-fiuoro-16j3-(piperidino-carbonyl)-A -17u-pregnen- 20-one.

Example VII 3,8 fluoro 1fi-carbomethoxy-A i7o:-pregnen20-one was treated following the technique described inExample V, except that dimethylamine was substituted by morpholine thus furnishing Elli-fluoro-16/3-(morpholino-carbonyl) d -17a-pregnen-20-onc.

4} Example VIII 3B fiuoro l6/3-carhornethoxy-A -17a-pregnen-20-one was treated in accordance with Example V, but using N- methyl aniline instead of dimethylamine, thus giving 3 3- fiuoro-16/3-(N-methyl-N-phenyl carbamyl)-A -17u-pregnen-ZO-one.

Example 1X 3,3 fluoro l6fi-carbomethoxy-A -17a-pregnen-20-onc was treated by the procedure of Example V, except that dimethylamine was substituted by N,N-diethylarnino ethylamine, thus furnishing 3B-fluoro-16fl-(N,N-diethylaminoethyl-carbamyl) -A 1 7u-pregnen-20-one.

Example X 3B chloro 16B-carbomethoxy-A -17a-pregnen-20-one and 3,8-bromo-l6fi-carbomethoxy-A -17a-pregnen-20-one were treated in accordance with Example IV, thus yield ing respectively: 3 ii-chloro-l6B-carbamyl-A -17a-pregnen- 20-one and 3/3-bromo-16fi-carbamyl-A -l7a-pregnen-20- one.

Example XI 35 chloro 16,8 carbornethoxy A 17a pregnen- 20-on-e and 3fi-bromo-16fl-carbomethoxy-A -17a-pregnen- 20-one were treated according .to Example V, giving respectively: 3,8 chloro 16 3 (dimethyl carba-myD- A 17a pregnen 2O one and 3B brorno 16B- (dimethyl carbamyl)-A -l7a-pregnen-20-one.

Example XII 3,6 chloro 16,8 carbomethoxy A 17m pregnen- 20-one and 3fl-bromo-16B-carbomethoxy-A -17a-pregnen- 20-one were tneated following the procedure described in Example VI, thus respectively producing 3,8-chlor0- 16/3 (piperidino carbonyl) [A 17oz pregnen 20- one and 3 3 brorno 16p (piperidino carbonyl) A 17a-pregnen-20-one.

Example XIII 3 3 chloro 16 3 carbomethoxy A 17oz pregnen- ZO-one and Bra-brorno-l6,6-carbometboxy-A -l7a-pregnen- 20-one were treated in accordance with Example VII, yielding respectively: 313 chloro 16B (morpholinocarbamyl) A a pregnen 2O one and 3fl-bromo- 16B-(morpho'lino-carbonyl)-A -17a-pregnen-20-one.

Example XIV The starting compounds of Example XIII were treated in accordance with Example VIII, thus furnishing respectively: 35 chloro 16B (N methyl N phenyl carbomyl) A 17oz pregnen 20 one and 3/3-bromol6fl-(N-methyl-N-phenyl carbamyl)-A -17a-pregnen-20- one.

Example XV The starting compounds of Example XIII were treated following the technique of Example IX, thus producing respectively: 3 8 chloro 16p (N',N diethylamino ethyl carbarnyl) A 17cc pregnen 2O one and 3/3 brorno 16,8 (N',N' diethylamino ethyl c-arbamyl)-A -17a-pregnen-20-one.

Example XVI same procedure, thus aflording the corresponding prod-.

ucts under II.

I claim: 1. A compound of the following formula:

wherein X is selected from the group consisting of fluorine, chlorine and bromine; R and R are selected from the group consisting of hydrogen, a lower alkyl, an amino lower alkyl, a lower alkylamino lower alkyl, a dilower alkylamino lower alkyl, an aryl containing up to 8 carbon atoms and an aralkyl group containing up to 8 carbon atoms, and R and R together with the nitrogen form a heterocyclic radical selected from the group consisting of piperidino, morpholino, pyrrolidino, and piperazino.

carbonyl) -A -17a-pregwherein X is selected from the group consisting of fluorine, chlorine and bromine; R and R are selected from the group consisting of hydrogen, a lower alkyl, an amino lower alkyl, a lower alkylamino lower alkyl, a di-lower alkylarnino lower alkyl, an aryl containing up to 8 carbon atoms and an aralkyl group containing up to 8 carbon atoms, and R and R together with the nitrogen form a heterocyclic radical selected from the group consisting of piperidino, morpholino, pyrrolidino, and piperazino.

12. 3fl-fluoro-16B-carbamyl-A -pregnen-20-one.

13. 3,8-chloro-16,8-carbamyl-A -pregnen-2O-one.

t '14. 3 B-brorno-16B-carbamyl-A -pregnen-20-one.

1 5. 3/8-flu0ro-16B-(dimethyl carbamyl) A -pregnen-20- 1 6. Sfi-chloro-IGB-(dimethyl carbamyl)-A -pregnen-20 il. 3,8-bromo-16/8-(dimethyl carbainyD-M-pregnen-ZO- :8. 3fi-fluoro-16/3-(piperidino carbonyl)-A -pregnen-20- one.

19. 35-chloro-16fi- (piperidino carbonyl) -A -pregnen-20- one.

20. 3fl-bromo-16fi-(piperidino carbonyl)-A -pregnen- 20-one.

No references cited. 

1. A COMPOUND OF THE FOLLOWING FORMULA: 